Heterocyclic compound and use



United States Patent 3,393,205 HETER'DCYCLIC COMPOUND AND USE Michael Cais, 21 Smolenskin St., Ahuza, Haifa, Israel, and William Taub, 43 Ben Zion St., Rehovoth, Israel No Drawing. Filed Feb. 15, 1966, Ser. No. 527,485 1 Claim. (Cl. 260-343.5)

ABSTRACT OF THE DISCLOSURE The compound 6,6-diethyl-4-iodo-2,3,5-trioxotetrahydropyran which is useful for preventing sludging of mammalian blood.

Cross-reference to related application The compound 6,6-diethyl-4-iodo-2,3,5-trioxotetrahyplication Ser. No. 274,928, filed Apr. 23, 1963, now US. Patent No. 3,344,150, granted Sept. 26, 1967.

This invention relates to a new method for the inhibition of sludging of blood, thrombus formation and platelet adhesiveness and, more particularly, to the novel chemical 6,6-diethyl-4-iodo-2,3,5-trioxotetrahydropyran and to its use for those purposes.

The new substance 6,6-diethyl-4-iodo-2,3,S-trioxotetrahydropyran, of this invention has valuable pharmacological properties in that, among other uses, it is an anti-inflammatory agent and an anti-coagulant and it prevents the sludging of mammalian blood by inhibiting thrombus formation and platelet adhesiveness. The 6,6-diethyl-4- iod'o-2,3,5-trioxotetrahydropyran of the present invention is thus useful as an antithrombotic agent.

The compound of the present invention has the tautomeric formulae is named 6,6 diethyl-3-iodo-2,3,S-trioxotetrahydropyran and is prepared by iodination (as with N-iodosuccinimide together with a catalytic amount of benzoyl peroxide in carbon tetrachloride) of 6,6-diethyl-2,3,5-trioxotetrahydropyran. The latter compound is prepared by the general procedure used to make the corresponding 6,6-dimethyl compound by Diels and Johlin, Ber. 44, 403-410 (1911) or by using known methods in the following reaction scheme:

M.P. 100.5101.5 C.

The following example will illustrate in detail a method of preparing the compound of the present invention.

3,393,205 Patented July 16, 1968 EXAMPLE 6,6-diethyl-2,3,S-trioxotetrahydropyran.ln a 3-neckcd flask fitted with stirrer, reflux condenser and dropping-funnel there were placed 6 g. (0.25 mole) sodium hydride and ml. dry diethyl ether. To the vigorously stirred mixture, 12 g. (0.25 mole) ethanol was added dropwise at such a rate as to maintain gentle reflux. After the addition of all the ethanol in the course of about one-half hour, the mixture was refluxed for another two hours by which time all the sodium hydride had reacted. To the cooled solution, 36.5 g. (0.25 mole) freshly distilled diethyl oxalate was added slowly and the mixture was stirred for another half-hour under cooling (ice-salt bath). At the end of this time 0.25 mole of diethyl-acetyl carbinol,

was slowly added to the continuously cooled and stirred reaction mixture; a short time after the beginning of this addition, the solution turned cloudy and a precipitate began to form. After the addition was completed, stirring was continued for another four hours. The reaction mixture was then poured into iced-water and the aqueous mixture was extracted twice with ether to remove unreacted materials. The aqueous layer was acidified with aqueous hydrochloric acid and the white-yellow precipitate formed was filtered to yield about 50 g. of 6,6-diethyl-2, 3,S-trioxotetrahydropyran. Crystallization from benzene yielded white crystals of M.P. 100.5-101.5 C.

If upon acidification of the aqueous mixture, the product is oily and does not crystallize, it is extracted with ether and dried over Na SO then the ether is evaporated and leaves the residue in crystalline form.

6,6-diethyl-4-iodo 2,3,5 trioxotetrahydropyran.A solution of 4.6 g. (0.025 mole) 6,6-diethyl-2,3,5-trioxo tetrahydropyran in 100 ml. chloroform was refluxed with 5.6 g. (0.025 mole) N-iodosuccinimide and a catalytic amount of benz-oyl peroxide for 30 minutes. After cooling and filtering, the filtrate was extracted with a 10% aqueous sodium bicarbonate solution. The combined aqueous layers were acidified with concentrated aqueous hydrochloric acid and the precipitate formed was collected by filtration. After recrystallization from methylene ch'loride/petroleum ether there was obtained 7.5 g. (96%) of 6,6-diethyl-4-iodo-2,3,S-trioxotetrahydropyran as a crystalline material of M.P. 156 C.

AnaZysis.-Calcd. for C H OJ: C, 34.87; H, 3.25; O, 20.64; I, 40.93. Found: C, 35.02; H, 3.50; O, 20.71; I, 40.89.

It is known that the white thrombi which form at sites of mechanical or other injury to the skin are principally composed of agglutinated (i.e. clotted) blood platelets which gradually fuse into a granular viscous substance. It is further known that a vascular defect occurs in advance of clotting, that such defect is related to platelet adhesiveness and that such adhesiveness is promoted by certain materials such as adenosine diphosphate (ADP).

As indicated above, it has now been found that the compound of this invention exhibits anticoagulation and antisludging properties (i.e. intravascular red ceil aggregation). Apparently these properties result from the action of the compound of this invention in counteracting ADP action and diminishing platelet adhesiveness but this is a matter of theory and not essential to the present invention.

Various tests were performed which demonstrated the ability of the compound of this invention to decrease sludging and to increase the suspension stability of mammalian blood. One of the principal methods used was a quantitative determination of erythrocyte sedimentation rate in Westergreen tubes, using a series of dilutions of plasma or artificial colloids. One part of washed human erythrocytes was suspended in two parts of each dilution of suspension fluid. The logarithm of sedimentation rate tions of the compound were added and the inhibition of aggregation was represented by a decrease in the sedimentation rate, measured in terms of the control sample. The results are illustrated in the following table.

TAB LE Compound Concentration in Sedimentation Percent mgm./cc. Blood Rate (l'lllIL/hl'.) Inhibition Control 38-57 1 15 61 G,6-Diethyl-2,3,5-trioxotetrahydropyrnn 0. 5 22 42 1 2 91 6,6-Diuthyl-4 iodo2,3,5t1'ioxotetrahydropyrau.. 0. 5 9 81 after one hour were plotted against the logarithms of the colloids concentration in the respective tubes. The points were approximately on straight lines with nearly the same slopes. The points where the line cut the abscissa gave the concentration of colloid which caused a sedimentation rate of l mm./hr. This parameter, called the critical concentration, is dependent on the colloids concentration in individual tubes and is considered a quantitative measurement of the erythrocyte aggregation power of the plasma. When the colloid concentration is lower than critical, the erythrocyte aggregation disappears and when the concentration is raised, aggregation and sedimentation rate rise very rapidly.

For the determination of the anti-aggregation properties of the compound of this invention, a fixed aggregation force was chosen, giving a sedimentation rate of 40 mm./hr. (using 1% Dextran). Increasing concentra- References Cited UNITED STATES PATENTS 3,336,339 8/1967 England 260-343.5

NICHOLAS S. RIZZO, Primary Examiner.

I. A. NARCAVAGE, Assistant Examiner. 

